George Cotsarelis, MD: ‘In men who are balding, the stem cell population is intact. When you compare it to the haired scalp, the balding scalp has similar numbers of stem cells.’

Decades of research into the biology of male pattern baldness has led hair loss expert George Cotsarelis, MD, to envision treatments for the condition. Those possible treatments could include inhibiting the PGD2 lipid, regenerating hair follicles by creating a wound-healing response, and tissue engineering.

Dr. Cotsarelis shared his research team’s extensive study of androgenetic alopecia during Sunday’s Marion B. Sulzberger, MD, Memorial Award and Lectureship, and in a separate interview.

“We discovered the location of the stem cells in the hair follicle in 1990. Since that time, I’ve tried to focus on understanding the biology of those cells and what they can do,” said Dr. Cotsarelis, Milton Bixler Hartzell professor of dermatology at the Perleman School of Medicine, University of Pennsylvania. “In men who are balding, the stem cell population is intact. When you compare it to the haired scalp, the balding scalp has similar numbers of stem cells.”

However, Luis Garza, MD, PhD, while a postdoctoral fellow working in the Cotsarelis lab, found that the progenitor cells — the daughter cells of the stem cells — are depleted in the balding scalp. The result is a tiny hair instead of a normal large hair.

“That raised the question of whether there was an inhibitor in the balding scalp that prevented the stem cells from proliferating, or a lack of an activator that just kept them very quiet and unable to turn into progenitor cells,” Dr. Cotsarelis said.

Dr. Cotsarelis’ laboratory also found that prostaglandin D synthase, which codes for the enzyme responsible for generating the prostaglandin D2 (PGD2) lipid, is elevated in balding scalp. “The levels of PGD2 are increased in balding scalp compared to nonbalding,” he said. “

The research team next applied PGD2 to knockout mice lacking one of the two PGD2 receptors, which showed that the PGD2 was acting through the DP2 receptor to inhibit hair growth, Dr. Cotsarelis said.

“It turns out the DP2 receptor was being studied in other systems, like the lung, because it is expressed on mast cells. Those cells are involved in allergies, like allergic rhinitis, and asthma,” he said.

Several new DP2 inhibitor drugs were developed to treat allergies, but were not efficacious. Dr. Cotsarelis’ research team is now working with a company that bought the rights to those drugs to test them as inhibitors to block PGD2 in the balding scalp.

“We have some promising results that could lead to a clinical trial using these inhibitors,” he said.

Regenerating hair follicles

Another possible approach to reversing hair loss is linked to the wound-healing response. Humans have evolved to repair injuries quickly to prevent blood loss, water loss, and infection. This mode of healing results in a scar rather than regeneration of skin with appendages, such as hair follicles.

“If you can get the skin to regenerate its hair follicles, then the scar is minimized and you end up with soft, normal-appearing skin. So, we are focusing on regenerating hair follicles,” Dr. Cotsarelis said. “We think the pathways that can regenerate skin are still present, but are being suppressed because of the way we have evolved. We are looking for molecular pathways, such as the Wnt pathway, which are important for normal regeneration of the skin by promoting hair-follicle regeneration.”

Tissue engineering

A third option for growing hair is to use tissue engineering of hair follicles. This would involve taking hair cells from a donor, growing them in culture, and re-implanting them. The hairs could be put into a scaffold to grow and then implanted, or the cells could be introduced in the scalp to grow new hair follicles, Dr. Cotsarelis said.

“I think that eventually we will be able to isolate hair follicle cells from someone’s scalp, grow them up, and increase their numbers, then use them for generating new follicles,” he said. “That is a little more long-term, but that is going to be an amazing technology we will be able to do.”

More than a quarter-century of research has been rewarding for Dr. Cotsarelis because of patients he has helped, and because of the personal satisfaction he has experienced in the laboratory.

“Doing research has been a privilege,” he said. “It is driven by the National Institutes of Health, which provides funding paid for by tax dollars. Since the government determines how it spends our tax dollars, we need to pay more attention to our elections. We need leaders to invest in the future of our country, but instead they have been effectively cutting the NIH budget. For a relatively small investment, NIH funding has led to major breakthroughs that improved the health of the people of our country, but NIH funding is in danger right now, and that reflects a problem with our political leadership that I hope will change.”

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